Dystonia and Parkinson's disease: What is the relationship?

Neurobiology of Disease 132 (2019) 104462

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Review

Dystonia and Parkinson's disease: What is the relationship? a

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Aakash S. Shetty , Kailash P. Bhatia , Anthony E. Lang

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Edmond J. Safra Program in Parkinson's Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Toronto, Canada Department of Clinical Movement Disorders and Motor Neuroscience, University College London (UCL), Institute of Neurology, Queen Square, London, United Kingdom

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ARTICLE INFO

ABSTRACT

Keywords: Dystonia Parkinson's disease Genetic PD syndromes

Dystonia and Parkinson's disease are closely linked disorders sharing many pathophysiological overlaps. Dystonia can be seen in 30% or more of the patients suffering with PD and sometimes can precede the overt parkinsonism. The response of early dystonia to the introduction of dopamine replacement therapy (levodopa, dopamine agonists) is variable; dystonia commonly occurs in PD patients following levodopa initiation. Similarly, parkinsonism is commonly seen in patients with mutations in various DYT genes including those involved in the dopamine synthesis pathway. Pharmacological blockade of dopamine receptors can cause both tardive dystonia and parkinsonism and these movement disorders syndromes can occur in many other neurodegenerative, genetic, toxic and metabolic diseases. Pallidotomy in the past and currently deep brain stimulation largely involving the GPi are effective treatment options for both dystonia and parkinsonism. However, the physiological mechanisms underlying the response of these two different movement disorder syndromes are poorly understood. Interestingly, DBS for PD can cause dystonia such as blepharospasm and bilateral pallidal DBS for dystonia can result in features of parkinsonism. Advances in our understanding of these responses may provide better explanations for the relationship between dystonia and Parkinson's disease.

1. Introduction Parkinson's disease (PD) is a neurodegenerative disease characterized by a movement disorder (i.e., the clinical syndrome of parkinsonism) as well as a wide variety of non-motor features, typically related to the deposition of alpha synuclein. The cause is largely unknown; the interaction of various genetic and environmental factors is usually proposed. However, PD is highly heterogeneous (e.g., clinical, genetic, pathology), suggesting that it is not a single disorder. Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both (Jinnah and Albanese, 2014). Dystonia is well recognized to be due to a large number of different causes; it can occur as an isolated clinical feature or can be associated with other neurological deficits, particularly in disorders that manifest parkinsonism (Albanese et al., 2013). Dystonia and Parkinson's disease are closely linked. Flexion postures of limbs and trunk are a primary manifestation of PD and were especially prominent in the pre-levodopa era. These sometimes resulted in marked deformities mistaken for joint diseases such as rheumatoid arthritis (MacFarlane and Dieppe, 1983). As discussed below, older literature often considered this as a form of dystonia (Denny-Brown, ⁎

1962; Denny-Brown, 1968), however, these postures are generally distinct from the movement disorder(s) now subsumed under the term dystonia (Albanese et al., 2013). Dystonia can be seen in 30% or more of patients with Parkinson's disease and it is more prevalent when the onset of parkinsonism is before the age of 40 (Kidron and Melamed, 1987; Hartmann et al., 1998; Quinn, 1993; Carella et al., 1993; Ishikawa and Miyatake, 2018). The dystonia can precede clinical symptoms of Parkinson's disease by almost a decade (Poewe et al., 2018; LeWitt et al., 1986). As indicated, parkinsonism and dystonia cooccur in a variety of disorders and, indeed, parkinsonism is commonly seen with mutations in DYT genes (e.g., DYT/PARK-TAF1 (DYT3), DYT/ PARK-ATP1A3 (DYT12), DYT/PARK-PRKRA (DYT16) including those involved in the dopamine synthesis pathway (e.g., DYT/PARK-GCH1 (DYT5a), DYT/PARK-TH (DYT5b) (Phukan et al., 2011; Wijemanne and Jankovic, 2015; Marras et al., 2016). 2. Pathophysiological overlap The pathophysiology of dystonia is not entirely understood and various theories and models have been proposed. Older hypotheses emphasized firing rates of neurons (Bergman et al., 1998) in the direct and indirect pathways involving the cortex-basal ganglia and thalamus

Corresponding author. E-mail address: [email protected] (A.E. Lang).

https://doi.org/10.1016/j.nbd.2019.05.001 Received 28 January 2019; Received in revised form 15 April 2019; Accepted 7 May 2019 Available online 09 May 2019 0969-9961/ © 2019 Elsevier Inc. All rights reserved.

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have suggested opposite states in dystonia and parkinsonism. Recent reviews have highlighted the importance of spatial and temporal patterns of activity in the GPi and STN in generating normal movements rather than the levels of output from these nuclei. Microelectrode recorded local field potentials (LFP) recordings from the GPi in patients with dystonia have demonstrated relatively high power in the 3- to 12Hz frequency range compared to other frequency bands. These lowfrequency oscillations have been suggested to be responsible for the pathophysiology of dystonia (Chu Chen et al., 2006). In PD, the LFP recorded during STN DBS surgery have demonstrated an increased oscillatory activity in the beta frequency band. The beta band is thought to be antikinetic and is abolished with dopaminergic therapy (Brown et al., 2001; Alegre et al., 2005; Silberstein et al., 2003), and DBS(Ray et al., 2008). The degree of clinical improvement correlates with the beta band suppression (Weinberger et al., 2006; Kühn et al., 2009). Along with suppression of beta band, there is an increase in theta, gamma and high-frequency band following dopaminergic therapy in PD (Brown et al., 2001; Foffani et al., 2003; Kane et al., 2009). Thus, there is an elevated relative power of the beta spectrum in PD, while the beta power is diminished in dystonia. The relative power in the 4- to 10-Hz frequency band is higher in dystonia compared to that reported in both treated and untreated PD (Silberstein et al., 2003). In addition to the above findings, less coherence between single-unit activity and LFP oscillations was noted in dystonia in comparison to PD patients and synchronization between neurons firing at beta frequencies is more prominent in PD than dystonia(Weinberger et al., 2012). In addition to the “firing rate model” and “firing pattern model” (Bergman et al., 1998), reduced movement-related inhibition (“dynamic activity model”) (Nambu et al., 2015) in the GPi has also been proposed. In the case of dystonia, signals through the hyperdirect, direct, and indirect pathways may cause a sequence of bursts and pauses in the GPi, with subsequent inhibition and rebound bursts in the thalamus and cortex leading to involuntary movements (“dynamic activity model”). The mechanism of underlying pathophysiological benefits for DBS is poorly understood, and various hypotheses (inhibition hypothesis, excitation hypothesis, and disruption hypothesis) have been proposed to explain the physiological mechanism of DBS (Vitek, 2008; Chiken and Nambu, 2015). It is unclear from our understanding of these pathophysiological changes in the basal ganglia how or why dystonia and parkinsonism can co-occur and why they can both respond to lesion/ DBS surgery. Confirming this state of ignorance, one review simply stated “GPi-DBS blocks abnormal information flow responsible for motor symptoms in both diseases” (Chiken and Nambu, 2015). To add the conundrum, chronic GPi DBS stimulation can sometimes paradoxically lead to parkinsonism in patients treated for dystonia (Zauber et al., 2009). This may be related to the distinctive outcomes of stimulation of different functional zones within the Gpi; ventral GPi stimulation is associated with improvement in dystonic symptoms at the possible cost of DBS-induced parkinsonism (Krack et al., 1998). Future explanations need to incorporate more recent concepts of dystonia as a network disorder involving the basal ganglia-cerebello-thalamo-cortical circuit (Poston and Eidelberg, 2012), as supported by many neuroimaging studies (e.g., FDG- PET, DTI), (Argyelan et al., 2009; Neumann et al., 2017) and the perhaps more recent proposals of the role of the cerebellum in the pathogenesis of dystonia (Kaji et al., 2018; Bologna and Berardelli, 2018, 2017). Recent studies, including the evaluation of local field potentials, have also suggested dysfunction of the spatial and temporal patterns of activity involving the SNr and the GPi, which modulate normal movements in both PD and dystonia (Vitek, 2008). In PD as well as dystonia, there is an alteration in both long-term potentiation and longterm depression modulating synaptic plasticity. Studies in PD mouse models have shown an absence of LTD in the striatum of dopaminedenervated mice and blocking of corticostriatal LTP in chronically

dopamine denervated mice (Centonze et al., 1999). The studies in animal models of dystonia have shown reduced LTD and increased LTP corticostriatal projections. These changes in the LTP and LTD can lead to abnormal motor activity (Calabresi et al., 2016). The dopaminergic system provides an important link between PD and dystonia. Reduced activity of the nigrostriatal dopamine system can cause both dystonia and parkinsonism. For example, pharmacological blockade of dopamine receptors can cause acute and tardive dystonia and drug-induced parkinsonism. Parkinsonism in monkeys induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is associated with foot dystonia similar to early PD (Perlmutter et al., 1997). Similarly, mouse models have shown the presence of dyskinesia and dystonia after 6-OHDA injections into the sensorimotor striatum (Lundblad et al., 2004). Many disorders combining dystonia and parkinsonism, including PD, are characterized by reduced levels of striatal dopamine due to loss of SNc neurons. Similarly, genetic disorders resulting in deficiencies of the enzymes involved in the dopaminergic synthesis pathway can present with dopa-responsive dystonia (DRD), parkinsonism in isolation, or both. Reduction in nigrostriatal dopamine results in increased activity of striatal cholinergic interneurons that regulate the activity of the striatal spiny projecting neurons which can give rise to abnormal striatal plasticity underlying both parkinsonism and dystonia (Dang et al., 2012; Healy et al., 2008a). There are also suggestions that two different affinity states of dopamine receptors could account for different clinical phenotypes. In the event of a marginal deficiency of dopamine or levodopa, the high-affinity receptors are stimulated without stimulation of the low-affinity receptors leading to dystonia in the absence of parkinsonism. When the dopamine depletion is severe, even the high-affinity receptors are not stimulated which leads to both parkinsonism and dystonia (Jankovic and Tintner, 2001). Large spiny cholinergic interneurons in the striatum also play a key role in direct and indirect pathways, modulating their output by influencing striatal dopaminergic and glutamatergic projections or by directly modulating striatal output via cholinergic receptors located on the medium spiny neurons (Calabresi et al., 2014). The concept of reciprocal interactions between dopamine and acetylcholine in the striatum was suggested in the 1960's and 1970's. Recent work supports the role of striatal cholinergic transmission in the control of voluntary movements (Bonsi et al., 2011) and dysfunction of acetylcholine release in the striatum is believed to be an important contributor to the symptoms of Parkinson's disease and dystonia (Pisani et al., 2007). Another aspect of striatal anatomy and the nigrostriatal dopamine system that could contribute to dystonia in PD relates to the striatal striasomal-matrix microstructure. Striosomes occupy 10–15% of the striatum with a caudo-rostral gradient, richest in the rostral striatum, while the dorsolateral (motor) putamen is mainly comprised of matrix (Johnston et al., 1990; Desban et al., 1993). Theoretically, patients with dystonia in PD (early or late) could have an imbalance in the activity of striosomal vs matrix spiny neurons, possibly due to more selective disturbances of nigrostriatal dopamine input to these regions (Sato et al., 2008). This concept has been discussed with respect to other forms of dystonia including that seen in advanced PD and in levodopainduced dyskinesia, as well as in other diseases such as Huntington's disease and X-linked dystonia parkinsonism DYT/PARK- TAF1 (DYT3) (Goto et al., 2005; Crittenden et al., 2016). Other neurotransmitters such as serotonin, acetylcholine, and glutamate may also play a role in patients presenting with parkinsonism and dystonia (Chase and Oh, 2000). 3. Dystonia in PD Parkinson's disease is associated with a variety of types of dystonia. We will begin this discussion with some general concepts and categories and then go on to a discussion dividing the dystonia into anatomical subtypes. This will be followed by a more detailed discussion of 2

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dystonia occurring in specific genetic forms of PD. The dystonia in PD infrequently occurs as a presenting symptom or an associated symptom in untreated PD patients. As mentioned earlier, dystonia as an initial manifestation, is more common in young-onset PD (LeWitt et al., 1986) and especially in autosomal recessive genetic parkinsonisms such as with PARK-PARKIN (PARK2) and PARK-SNCA (PARK1) mutations. Early dystonia can have a variety of focal and segmental distributions, particularly involving the lower limb. Exertion (e.g., walking) may be a precipitant or trigger for the dystonia. Patients can also develop fixed painless contractures of limbs, which are also thought to be dystonic. Dystonia can precede the development of parkinsonism from anywhere between 1 and 25 years but on an average 10 years in one review (Tolosa and Compta, 2006), although this is considerably longer than in our experience. The response of early dystonia to the introduction of dopamine replacement therapy (levodopa, dopamine agonists) is also variable; it can worsen, improve or remain unchanged (LeWitt et al., 1986); some have suggested a better response to dopamine agonists but this benefit is inconsistent. More commonly, dystonia occurs in PD patients sometime after levodopa has been initiated. A variety of patterns of levodopa-associated dystonia occur in PD: when the medication is wearing off, at peak dose or at the onset and/or off-set of benefit as a part of diphasic dyskinesia. Approximately 30% of the PD patients treated with levodopa develop “off- dystonia (Kidron and Melamed, 1987). One common variant of this occurs in the morning before the first dose is taken. In contrast to the other varieties, off-dystonia is commonly painful. Off-dystonia is more common in the foot (Melamed, 1979) while peak-dose dystonia involves the neck, face and upper limbs. The dystonia occurring as part of diphasic dyskinesia tends to involve the lower limbs. Dystonia can also occur in patients who have undergone DBS as a consequence of stimulation but the majority of these symptoms are secondary to the diffusion of the current into the corticospinal or corticobulbar fibres (Baizabal-Carvallo and Jankovic, 2016). “Apraxia of eyelid opening”, which in many patients is probably a form of pre-tarsal blepharospasm (as supported by response to pre-tarsal injections of botulinum toxin), is seen in 2–31% of the patients undergoing STN DBS (Tommasi et al., 2012; Fuß et al., 2004; Umemura et al., 2011). Occasionally this symptom responds to levodopa (Umemura et al., 2008) or lowering stimulation parameters or increasing the frequency of the stimulation (Strecker et al., 2008) (Table 1).

Blepharospasm and “eyelid opening apraxia” are more common in atypical parkinsonian syndromes than in PD. The incidence of blepharospasm in PD has been reported between 0.9%–3.26%; it may very rarely precede the disease and can be levodopa responsive (Rana et al., 2012; Yoon et al., 2005). There is a single case report of Meige syndrome in Parkinson's disease (Mark et al., 1994).

Anterocollis refers to a forward flexion of the head and neck. It can be mild and be seen as a part of the stooped posture of PD; severe anterocollis is usually associated with disproportionate flexion of the head and neck in comparison to the posture of the limbs and trunk (Quinn, 1989; van de Warrenburg et al., 2007a). Anterocollis is more common in Multiple System Atrophy (MSA) with a prevalence of 42.1% (Ashour and Jankovic, 2006) while a much lower prevalence is reported in PD (5.8%) (Kashihara et al., 2006; Fujimoto, 2006). It affects certain ethnicities more frequently, with a higher prevalence of case reports from Japan. Anterocollis in PD and MSA does not improve with sensory tricks (Boesch et al., 2002). It is more commonly seen in longstanding cases of PD, where it is often combined with pronounced head tilt and possibly some rotation, but rarely can present before the onset of motor symptoms of PD (Kashihara et al., 2006). Pisa syndrome is characterized by marked lateral flexion of the trunk, which resolves on lying down. It was previously described as an adverse effect of dopamine blocking agents (Ekbom et al., 1972) but it is now known to be associated with PD (Villarejo et al., 2003). Scoliosis is more prevalent in PD than in the general elderly population (prevalence of 8.5–60% in PD) (Ashour and Jankovic, 2006; Baik et al., 2009; Serratrice and Schiano, 1976; Grimes et al., 1987; Duvoisin and Marsden, 1975). Pisa syndrome may precede scoliosis in PD. Pisa syndrome may have a variable response to botulinum toxin (Bonanni et al., 2007) and DBS surgery (Umemura et al., 2010). Occasionally patients respond to the combination of DBS surgery and levodopa (Artusi et al., 2017). There are rare reports of development of Pisa syndrome following pallidotomy (Spanaki et al., 2010; van de Warrenburg et al., 2007b). However, these were secondary to malplaced pallidotomies (van de Warrenburg et al., 2008). Complex corrective spinal surgery can successfully improve the camptocormic posture but is associated with a very high complication rate (Chan et al., 2018; Wadia et al., 2011). Some cases of camptocormia (Mano, 2018), Pisa syndrome (Cannas et al., 2009) and particularly anterocollis, seem to be induced by changes in dopaminergic therapy, particularly dopamine agonists (even chronic therapy that had, to date, been tolerated well), as supported by resolution of the symptoms on drug withdrawal (Prakash and Lang, 2007). Anterocollis has also been reported secondary to levodopa and amantadine (Kataoka and Ueno, 2011; Dohm et al., 2013; Taguchi et al., 2008), as an “off” phenomenon (Guduru et al., 2017) or secondary to dyskinesia due to dopaminergic therapy associated with fluctuations in anterocollis (Doherty et al., 2011). Postural deformities in PD may be secondary to central mechanisms like dystonia, rigidity and proprioceptive disintegration while peripheral causes such as myopathy and skeletal and soft tissue changes may also play a role (Doherty et al., 2011). Indeed, it is still debated whether the development of camptocormia and anterocollis are secondary to dystonia, myopathy (Spuler et al., 2010; Laroche and Cintas, 2010; Margraf et al., 2010) or both.

3.2. Camptocormia, Pisa syndrome and anterocollis in PD

3.3. Limb dystonia in PD

Camptocormia refers to extreme flexion of the trunk while sitting which worsens on walking and improves in the supine position (Jankovic, 2010). Although recognized since the time of Charcot, the first case series in PD was reported in 1999 by (Djaldetti et al., 2001). Camptocormia may improve with a geste antagoniste, botulinium toxin (von Coelln et al., 2008; Azher and Jankovic, 2005) and DBS surgery suggesting dystonia as a possible explanation in at least a proportion of cases (Sako et al., 2009). Similarly EMG studies have shown excessive activation of abdominal muscles (Bloch et al., 2006). Abnormal control of the reticulospinal tract by the basal ganglia has been proposed as a pathogenic mechanism (Lepoutre et al., 2006). Abdominal, hip and spine surgery have been described as the triggering events for the camptocormia (Djaldetti et al., 2001; Bloch et al., 2006; Lepoutre et al., 2006; Tiple et al., 2009).

Around 10–15% of PD cases present with focal dystonia of the limbs (Wickremaratchi et al., 2011). Involvement of the lower limb is more common than upper limb. Lower limb dystonia can be the initial presentation of typical “idiopathic” Parkinson's disease, young-onset genetic parkinsonism (PARK-PARKIN (PARK2), PARK-PINK1 (PARK6), PARK-DJ1 (PARK7) mutations) and dopa-responsive dystonia, clearly highlighting common dopaminergic pathophysiological mechanisms (Healy et al., 2008b; Schneider et al., 2006; Elia et al., 2014; Chang and Josephs, 2013). Very rarely, paroxysmal exercise-induced dystonia can be the presenting symptom or be part of the clinical syndrome of PD, particularly in young onset cases as due to PARK-PARKIN (PARK2) gene mutations (Erro et al., 2014). Patients can demonstrate a “pseudo-foot drop gait” secondary to the action dystonia of the plantar flexors and the foot invertors triggered while walking (Aquino et al., 2015).

3.1. Blepharospasm in PD

3

4

5.3–6.0%(Bloch et al., 2006; Lepoutre et al., 2006)

Anterocollis

10–15%(Taguchi et al., 2008)

3–17.6%(Djaldetti et al., 2001; Sako et al., 2009)

Camptocormia

Limb dystonia

0.7% in PD(Tommasi et al., 2012) 2–31% in STN DBS(Goto et al., 2005; Crittenden et al., 2016; Chase and Oh, 2000)

Eyelid opening apraxia

8.5–60%(Sako et al., 2009; Ashour and Jankovic, 2006; Kashihara et al., 2006; Fujimoto, 2006; Boesch et al., 2002) (scoliosis)

0.9–3.26% (Baizabal-Carvallo and Jankovic, 2016; Tommasi et al., 2012)

Blepharospasm

PISA syndrome/scoliosis

Frequency of dystonia in PD

Type of dystonia

Table 1 Summary of dystonia in Parkinson's disease.

Atypical parkinsonism - MSA

2) Cervical spine pathology.

Fixed deformity Ankylosing spondylitis Vertebral pathology Syrinx Idiopathic or degenerative scoliosis. 1) Concomitant myopathy Anterior horn cell disease.

2) -

1) Concomitant myopathy Anterior horn cell disease. (associated with trunk extension weakness)

–

–

Differential diagnosis

More common in advanced PD. Triggers Abdominal, spine, hip surgery. changes in dopaminergic therapy chronic dopaminergic therapy (specially dopamine agonist).

Related to medications: Off dystonia. Diphasic dyskinesia.

2) Paroxysmal exercise-induced dystonia.

Other drugs: valproic acid, antidepressants and cholinesterase inhibitors 1) Task specific/action-induced dystonia Upper limbs – writer's cramp, musician's dystonia. Lower limbs: pseudo foot drop gait.

- Drugs - changes in dopaminergic therapy - chronic dopaminergic therapy (specially dopamine agonist). - Initiation of dopaminergic medication.

- 4-9 years after pallidotomy (2 case reports)

- changes in dopaminergic therapy - chronic dopaminergic therapy (specially dopamine agonist). - Off-period dystonia. - As a manifestation of levodopa-induced dyskinesia Triggers

More common in advanced PD. Triggers

-

- May precede PD. - Commonly associated with eyelid opening apraxia.

Characteristics

Botulinium toxin. Optimization of dopaminergic therapy. STN DBS - inconclusive. Clozapine.

-

- Optimization of dopaminergic therapy.

- Botulinium toxin.

Botulinium toxin may be helpful. Withdrawal of dopamine agonist. Clonazepam (one case report) DBS Spine fusion (last resort)

-

- May respond to levodopa and fluctuate with treatment response. - Good response to Botulinium toxin. - May respond to levodopa. - Reducing stimulation and increasing frequency in STN DBS patients. - Good response to Botulinium toxin (pretarsal injections). - Rarely responds to levodopa. - Botulinium toxin – variable response. - DBS- varied outcomes.- Spinal surgery (last resort)

Treatment

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Neurobiology of Disease 132 (2019) 104462

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Dystonia of the upper limb in PD can be task specific although non-task specific dystonia is more common. Both musician's dystonia and taskspecific writing tremor preceding the development of overt Parkinson's disease have been described (Smith et al., 2014; Castro Caldas et al., 2016). Deformities of the limb (often referred to as “striatal” postures) were originally described by (Charcot, 1877) and (Purves-Stewart, 1898) in patients with Parkinson's disease. Their true prevalence is unknown. It is unclear whether some of these abnormal postures represent forms of dystonia; older literature sometimes described “flexion dystonia” of PD, or “hemiplegic dystonia” of pyramidal tract lesions, which are now clearly distinguishable from the modern concept of dystonia. Given some uncertainty in the origin and classification of “striatal limbs” we will discuss these features briefly here. As will be seen, there is clear overlap between these postures and dystonia, especially in the case of the “striatal toe”. The typical deformity seen in the “striatal hand” is the flexion of the metacarpophalangeal joints, extension of the proximal interphalangeal joints, flexion of the distal interphalangeal joints, and ulnar deviation (Gortvai, 1963). Striatal hand deformities in PD have been reported in 12.8% in one series (Ashour and Jankovic, 2006) while 24% in another series (Reynolds and Petropoulous, 1965). While Kyriakides and Langton reported only 3 cases of hand deformity in PD over a one year period at a “busy” neurology department (Kyriakides and Hewer, 1988). The variability in these numbers may be related to a variable definition of striatal hand in these series. In contrast to dystonia associated with PD, which classically worsens with activity and disappears during sleep, the striatal hand is present at rest and persists during sleep. Untreated dystonia can develop fixed postures, which are different from striatal posturing. Rigidity (Kyriakides and Hewer, 1988) and dystonia (Tolosa & Compta, 2006) have been postulated as the mechanism for these postures, but the exact mechanism is still debated. Striatal hand is classically seen in advanced PD but can also be seen in early stages typically associated with mild flexion of metacarpophalangeal joints of the hand (Ashour and Jankovic, 2006; Ashour et al., 2005). The striatal hand can cause disfigurement, pain, and loss of function in severe cases. Flexion deformities of the fingers can cause skin erosions and secondary infections in the palm. The “striatal foot” is associated with hallucal hyperextension, flexion of the other toes and ankle inversion (Ashour and Jankovic, 2006). The flexion of the toes typically described as the toe-curling symptom is usually associated with pain and cramps. It also impairs the ability to wear shoes, walk and stand. It occasionally can cause ulceration and bone erosion. It can precede levodopa therapy in 2.4%- 8% of the patients (Kidron and Melamed, 1987; Nausieda et al., 1980) and needs to be differentiated from dystonia associated with levodopa therapy. An isolated “striatal toe” is a subtype of striatal foot in the absence of the equinovarus foot. It needs to be differentiated from the Babinski sign which is usually associated with toe fanning and flexion synergy of other muscles in the same leg along with hallucal hyperextension (Winkler et al., 2002). Dystonia, rigidity (Kyriakides and Hewer, 1988) and inappropriate muscle contraction (Hu et al., 1999) may be responsible for the striatal foot. Striatal limbs rarely respond to antiparkinsonian drugs, but there are some case reports of complete resolution of striatal hand with levodopa treatment (Ashour et al., 2005) and the apparent current low incidence of the striatal hand and Parkinsonian hand deformities in particular, suggests that modern dopaminergic therapy may prevent the occurrence of these features, which were more common in the pre-levodopa era. On the other hand, rarely, dopaminergic drugs previously used in PD (pergolide and bromocriptine) were associated with reactive fibrosis sometimes leading to limb contractures (Quinn et al., 1988). Other medications like anticholinergics, baclofen, and benzodiazepines have been successful in treating foot dystonia but their response in striatal limbs has not been reported. Botulinum-toxin injection has been

used successfully in the treatment of striatal toes (Giladi et al., 1994; Jankovic, 2004). Botulinum-toxin injection for striatal hand, especially into the lumbricals and short adductors of the thumb, has led to functional improvement, pain relief and prevention of injuries secondary to finger contractures (Cordivari et al., 2001). Improvement in striatal limb deformities has been reported with neurosurgical treatments such as thalamotomy (Gortvai, 1963), and DBS (Morishita et al., 2008). Orthopedic surgical interventions and spints can be attempted if conventional non-operative treatments are unsuccessful (Moore et al., 1998). 3.4. Cervical dystonia in PD Typical cervical dystonia (distinct from anterocollis) rarely can be the presenting symptom and can precede other features of PD by 5.8 ± 7.6 years with mean age of onset of parkinsonism of 49.1 ± 10.1 years (Papapetropoulos and Singer, 2006). Torticollis (rotation) has been the most common phenotype seen in the patients with PD. These patients have responded well to the botulinium toxin and generally have not experienced worsening of dystonia with initiation of the levodopa treatment (Papapetropoulos and Singer, 2006). 4. Genetic PD syndromes and dystonia 4.1. Autosomal dominant 4.1.1. Park-SNCA (PARK1) PARK-SNCA (PARK1) related PD can be secondary to mutations or multiplications of the alpha synuclein gene. This form of genetic PD is characterized by earlier age of onset of disease and motor fluctuations with a higher prevalence of non-motor symptoms and relatively early decline of levodopa responsiveness (Oczkowska et al., 2013). In a recent meta-analysis, dystonia was noted in 12 out of 146 cases along with features of parkinsonism (Trinh et al., 2018). Dystonia may be seen earlier in the disease course in comparison to sporadic PD. Foot and cervical dystonia along with blepharospasm have been reported in these patients (Kiely et al., 2015; Konno et al., 2016). 4.1.2. Park-LRKK2 (PARK8) PARK-LRKK2 (PARK8) mutations are the most common genetic cause of PD. In a case-control study of patients with PARK-LRKK2 (PARK8) conducted in 21 centers the incidence of dystonia was 42% (126 out of 301), the majority of them with “off period” foot dystonia early in the disease (Healy et al., 2008a). Rarely, patients with blepharospam, arm, neck and lingual dystonia have been reported with PARK-LRKK2 (PARK8) mutations (Healy et al., 2008a). A recent metaanalysis showed a similar incidence of dystonia (38%; 61 out of 161 cases) (Trinh et al., 2018). 4.1.3. Park-GBA Gaucher's disease is an autosomal recessive disorder secondary to mutations in the PARK-GBA gene. Both homozygous and heterozygous mutations confer significant risk for the development of PD. Parkinsonism secondary to PARK-GBA mutations is associated with earlier age of onset, higher incidence of cognitive impairment and rapid motor decline (Brockmann et al., 2011; Brockmann et al., 2014; Beavan et al., 2015). Dystonia has not been specifically reported in patients with parkinsonism secondary to PARK-GBA mutations. However, apart from the differences noted above, PARK-GBA -associated PD is typical levodoparesponsive Lewy body disease and so the various forms of dystonia, particularly those beginning after levodopa initiation, probably occur in a similar fashion to non-GBA-associated PD. Interestingly, a recent study showed an increased incidence of PARK-GBA mutations and decreased GBA activity in a series of patients with dystonia without parkinsonism suggesting an independent role in dystonia (Schreglmann 5

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et al., 2018).

neurodegeneration (PLAN). There are three main phenotypes:1) infantile-onset neuroaxonal dystrophy (INAD); 2) an atypical later-onset form (atypical NAD); and 3) young-onset dystonia-parkinsonism (PLAN-DP) (Karkheiran et al., 2015; Paisan-Ruiz et al., 2009; Kurian et al., 2008). Rarely they can present with motor symptoms after the age of 40 (Klein et al., 2016). NBIA/DYT/PARK-PLA2G6 (NBIA1,PARK14) patients universally present with parkinsonism and dystonia can be seen in the majority of the patients, including retrocollis/opisthotonus. Other features such as tremors, ataxia, pyramidal signs, autonomic disturbances, cognitive and behavioral issues are typically also present (Karkheiran et al., 2015; Paisán-Ruiz et al., 2012). A small proportion of patients with NBIA/DYT/PARK-PLA2G6 (NBIA1,PARK14) mutations have presented with pure young-onset parkinsonism, diagnosed as having PD (YOPD). Further encouraging this diagnosis has been the clear benefit obtained with levodopa and the later development of levodopa-induced dyskinesia (also features of some patients with a more obvious diagnosis of PLAN-DP). Pathologically there can be the presence of neuroaxonal dystrophy and widespread alpha-synuclein pathology with Lewy bodies and Lewy neurites particularly in the neocortex. Tau pathology can also be infrequently present (Klein et al., 2016; Paisán-Ruiz et al., 2012; Miki et al., 2017). Importantly, in some patients, the Lewy pathology has been so typical of PD that a diagnosis YOPD was reported initially and the correct diagnosis was made only much later when genetic testing became available (Klein et al., 2016; Tabamo et al., 2000). A number of other AR disorders are associated with an atypical dystonia-parkinsonism syndrome {e.g., PARK-ATP13A2 (PARK9), PARK-FBX07 (PARK15) and NBIA/DYT-PANK2 (NBIA1)} that would generally not be mistaken for the genetic parkinsonisms described above (Schneider et al., 2009) (Table 2).

4.1.4. Park-VPS35 (PARK17) PARK-VPS35 (PARK17) was initially reported in a Swiss family in 2008 by (Wider et al., 2008). Only two cases were reported to manifest dystonia in a recent meta-analysis of PARK-VPS35 (PARK17) (in most of the other 65 cases the information was not available) (Trinh et al., 2018). 4.1.5. Park-DNAJC13 (PARK19) PARK-DNAJC13 (PARK19) mutations were initially recognized in 2014 in a Mennonite family of Dutch–German–Russian ancestry (Vilariño-Güell et al., 2014). These mutations typically present with late-onset parkinsonism indistinguishable from sporadic PD. Dystonia seems to be very rare with these mutations. PARK-DNAJC13 (PARK19) mutations can rarely present with lower limb dystonia (Vilariño-Güell et al., 2014). 4.2. Autosomal recessive 4.2.1. Park-PARKIN (PARK2) Mutations in PARK-Parkin (PARK2) are probably the most commonly defined cause of early-onset Parkinson's disease (EOPD). This disorder is characterized by early dystonia (i.e., before levodopa initiation), slow progression, brisk reflexes, neuropsychiatric symptoms, the absence of Lewy bodies and an excellent response to levodopa with the early development of motor complications. In one large series dystonia was observed in 41% of the patients as an initial symptom, commonly involving the lower limbs but uncommonly also involving the neck, trunk, and hands. Eventually, 78% of patients developed dystonia at some point prior to the initiation of treatment d (Khan et al., 2003). Rarely PARK-Parkin (PARK2) mutations can present with isolated lower limb dystonia mimicking DYT-TOR1A (DYT1) or DRD. The foot dystonia is usually task-specific, brought out and worsened by walking or exercise and sometimes this can progress to involvement at rest (Elia et al., 2014). Occasional patients can present with foot drop dystonia (de Schipper et al., 2015).

5. Role of GTP-cyclohydrolase1 and Tyrosine hydroxylase mutations in PD 5.1. DYT/PARK-GCH1 (DYT5a) and PD GTP-cyclohydrolase1(GCH1) is the rate limiting enzyme in the synthesis of tetrahydrobiopterin (BH4) which is a cofactor for tyrosine hydroxylase. Classically, GCH1 deficiency (the commonest cause of DRD) presents with lower limb dystonia in children with an excellent response to low doses of levodopa. Many of these patients demonstrate features of bradykinesia and postural instability prior to levodopa initiation. Some patients, especially those with a later presentation (even into adult life), can present a pure parkinsonian syndrome with little or no dystonia. As in patients with the classical DRD presentation, these patients typically do not develop motor fluctuations or levodopa-induced dyskinesias and have no evidence of pre-synaptic nigrostriatal degeneration (e.g., as seen on F-dopa or dihydrotetrabenazine PET or dopamine transporter SPECT). The small number of postmortem studies available confirm a lack of neurodegeneration (i.e., a normal number of nigral neurons) but reduced neuromelanin staining in the substantia nigra along with reduced levels in neopterin and biopterin in the brain (Rajput et al., 2018; Furukawa et al., 1999). However, recently there has been increasing interest in the possible association between DYT/PARK-GCH1 (DYT5a) mutations and a second, degenerative form of parkinsonism (Guella et al., 2015; Lewthwaite et al., 2015; Furukawa and Kish, 2015). A study by (Mencacci et al., 2014) described four families with DRD/DRD with parkinsonism or parkinsonism in isolation. The patients with parkinsonism had an abnormal dopaminergic scan suggestive of presynaptic dopamine neuronal degeneration. A whole genome study in patients with parkinsonism demonstrated that rare DYT/PARK-GCH1 (DYT5a) coding variants were associated with a seven-fold increase in the risk of Parkinson's disease. There are also studies to suggest DYT/PARK-GCH1 (DYT5a) to be a low-risk susceptibility locus for PD (Nalls et al., 2014). There are other rare phenotypes reported with DYT/PARK-GCH1

4.2.2. Park-PINK1 (PARK6) Mutations in PARK-PINK1 (PARK6) are the second most common cause of autosomal recessive (AR) EOPD, and over 62 disease-causing variations have been described with this gene (Kasten et al., 2018). They have a very similar presentation to PARK-Parkin (PARK2) mutations most likely including dystonia, as described above, given the important overlapping pathophysiological mechanism of these two genes in the mitophagy pathway (Jin and Youle, 2012) but with a higher incidence of psychiatric manifestations especially depression and anxiety which are seen in 1/3rd of patients. There is very little literature on dystonia in PARK-PINK1 (PARK6)-related PD and a review of the MDSGene database found dystonia reported in approximately 21% (29 out of 139 cases) of the patients, unrelated to levodopa in a majority of the cases (Kasten et al., 2018). 4.2.3. Park-DJ1 (PARK7) PARK-DJ1 (PARK7) mutations are associated with young-onset parkinsonism with 46% of the patients having associated dystonia. The dystonia in PARK-DJ1 (PARK7) -related PD can present with early-onset lower limb dystonia (Bonifati et al., 2003a). There is a single case report of late-onset lower limb dystonia and the same patient also had predominant craniocervical dystonia (Taipa et al., 2016). Blepharospasm has been reported in few cases with PARK-DJ1 (PARK7) mutations (Bonifati et al., 2003b; van Duijn et al., 2001). 4.2.4. NBIA/DYT/PARK-PLA2G6 (NBIA1,PARK14) NBIA/DYT/PARK-PLA2G6 (NBIA1,PARK14) mutations are associated with autosomal recessive phospholipase-associated 6

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A.S. Shetty, et al.

Table 2 Dystonia in genetic PD. Genetic mutation

Frequency of dystonia

Body part affected

Autosomal dominant PARK-SNCA (PARK1)

8.2% (Jankovic, 2004)

PARK-LRKK2 (PARK8)

38–42%(Jankovic, 2004; Moore et al., 1998)

PARK-VPS35 (PARK17)

Uncommon

Foot Cervical Blepharospasm (Cordivari et al., 2001; Morishita et al., 2008) “Off period”- foot dystonia (most common). Blepharospasm. Cervical Lingual (Moore et al., 1998).

Autosomal recessive PARK-Parkin (PARK2)

41%- 70% (Wider et al., 2008)

PARK-DJ-1 (PARK7)

46% (Brockmann et al., 2014)

PARK-PINK1 (PARK6) PARK-DNAJC13 (PARK19) NBIA/DYT/PARK-PLA2G6 (NBIA2, PARK14)

21%(Brockmann et al., 2014) Uncommon Unknown

Foot dystonia - Can be task-specific (worsened on walking/exercise) (Spuler et al., 2010). - Pseudo foot drop dystonia (Brockmann et al., 2011). Foot (Schreglmann et al., n.d.) Craniocervical(Khan et al., 2003). Blepharospasm(de Schipper et al., 2015; Kasten et al., 2018) Foot dystonia Lower limb dystonia - unspecified (Oczkowska et al., 2013). Limb dystonia - unspecified (Bonifati et al., 2003a; Paisan-Ruiz et al., 2009)

no reported associations between PD and other genes involved in the bioamine synthesis pathway that cause varying DRD and parkinsonian phenotypes.

(DYT5a) mutations. (Ceravolo et al., 2013) described three phenotypes in the same family: the index case with an MSA-like presentation, his son with young-onset classic DRD and his brother with late-onset parkinsonism mimicking PD. In another report, (Guella et al., 2015) described an 82-year-old lady with parkinsonism and an asymmetrical onset of tremors. She died at 90 years with autopsy demonstrating neurofibrillary tangles suggestive of PSP but also synuclein deposition in the brainstem. Finally, (Lewthwaite et al., 2015) described a patient presenting with adult-onset parkinsonism associated with an abnormal DAT-scan, dyskinesia and dementia. Other members of the family had pure DRD without parkinsonism and normal scans. Although it is unclear whether these rare examples are true or simply coincidental associations, they have encouraged hypotheses as to how DYT/PARKGCH1 (DYT5a) deficiency might predispose to a neurodegenerative process. BH4 is a cofactor for nitric oxide synthase. Reduced levels of BH4 may cause an increase in NOS uncoupling and increased production of reactive oxygen species, which can result in oxidative stress and neurodegeneration (Giasson et al., 2000; Ryan et al., 2013). Reduced GCH1 activity can lead to mitochondrial dysfunction and alpha-synuclein aggregation. Genetic and environmental factors modulate the outcome of GCH1 deficiency. Age-related decline and chronic dopamine deficiency may eventually predispose dopaminergic cells to early neurodegeneration (Furukawa & Kish, 2015).

6. Role of DYT-TOR1A(DYT1) in PD DYT-TOR1A (DYT1) mutations are responsible for early-onset, generalized dystonia (Ozelius et al., 1997). Almost all cases are due to a GAG deletion that removes 1 amino acid from torsinA (delE303) (Ozelius et al., 1997; Ozelius et al., 1989). Clinically it presents with early onset limb dystonia which later can generalize with usual sparing of the craniocervical region (Bressman et al., 2002). DYT-TOR1A (DYT1) never presents with parkinsonism and previous studies have failed to show the mutation in young-onset parkinsonism (Leung et al., 2001; Yang et al., 2009). The protein Torsin A is a member of the AAA+ (ATPases Associated with a variety of cellular Activities) superfamily and performs a chaperone-like function including protein trafficking, folding and membrane fusion (Breakefield et al., 2008; Standaert, 2011; Breakefield et al., 2001). TorsinA has been found in Lewy bodies which has been confirmed by immunocytochemistry, and it is postulated that Torsin A may be responsible for neuronal dysfunction in PD (Shashidharan et al., 2000; Sharma et al., 2001)Although initially promising, further studies have failed to replicate the proposed protective effects of Torsin1A in mouse models(Li et al., 2012).

5.2. DYT/PARK-TH (DYT5b) and PD

7. Conclusion

Tyrosine hydroxylase is an iron containing monooxygenase enzyme catalyzing the rate-limiting step in the synthesis of catecholamines. Tyrosine hydroxylase requires tetrahydrobiopterin as a co-factor for this process. TH deficiency can present with symptoms indistinguishable from classical dopa-responsive dystonia. It can also present with infantile parkinsonism with delayed development (Lüdecke et al., 1996; Swaans et al., 2000) or severe progressive encephalopathy (Hoffmann et al., 2003). There are a few case reports of TH deficiency presenting with levodopa-responsive myoclonus dystonia (Stamelou et al., 2012). There is a single case report of a DYT/PARK-TH (DYT5b) deletion leading to haploinsufficiency in a 54 year old gentleman with levodopa responsive PD in the absence of dystonia. As with DYT/PARK-GCH1 (DYT5a) mutations, various hypotheses have been proposed linking disturbances of TH with PD (e.g., (Kawahata et al., 2015) (Kastner et al., 1993)). To date, there have been

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